home > drugs a-z list > bexxar (tositumomab and iodine 1131 tositumomab) drug center > bexxar (tositumomab and iodine 1131 tositumomab) drug - clinical pharmacology

Mechanism of Action

Tositumomab binds specifically to an epitope within the extracellular domain of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B lymphocytes to mature B lymphocytes) and on B-cell non-Hodgkin's lymphomas. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding. The BEXXAR therapeutic regimen induces cell death by emitting ionizing radiation to CD20-expressing lymphocytes or neighboring cells. In addition to cell death mediated by the radioisotope, other possible mechanisms of action include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and CD20-mediated apoptosis.

Pharmacodynamics

In two clinical studies (one in chemotherapy-naive patients and one in heavily pretreated patients), the administration of the BEXXAR therapeutic regimen resulted in sustained depletion of circulating CD20-positive cells. The assessment of circulating lymphocytes in these patients did not distinguish normal from malignant cells; consequently, recovery of normal B cell numbers was not directly assessed. At 7 weeks following treatment, the median number of circulating CD20-positive cells was zero (range: 0 to 490 cells/mm³) with recovery beginning at approximately 12 weeks. At 6 months following treatment, 8 (14%) of 58 chemotherapy-naive patients and 6 (32%) of 19 heavily pretreated patients had CD20-positive cell counts below normal limits. There was no consistent effect of the BEXXAR therapeutic regimen on post-treatment serum IgG, IgA, or IgM levels.

Pharmacokinetics

A pharmacokinetic study of I-131 tositumomab determined that a 475-mg predose of unlabeled antibody decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. The median blood clearance following administration of 485 mg of tositumomab in 110 patients with non-Hodgkin's lymphomas was 68.2 mg/hr (range: 30.2 to 260.8 mg/hr). Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have a larger volume of distribution, faster clearance, and shorter terminal half-life. The total body clearance, as measured by total body gamma camera counts, was dependent on the same factors noted for blood clearance. Patient-specific dosing, based on total body clearance, provided a consistent radiation dose despite variable pharmacokinetics, by allowing each patient's administered activity to be adjusted for individual patient variables. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with non-Hodgkin's lymphoma was 67 hours (range: 28 to 115 hours).

Elimination of Iodine-131 occurs by decay (Table 5) and excretion in the urine. Five days following the dose, the whole body clearance was 67% of the injected dose. Ninety-eight percent (98%) of the clearance was accounted for in the urine.

Clinical Studies

The clinical benefit of the BEXXAR therapeutic regimen was established in 2 single-arm clinical trials conducted in 100 patients with low-grade, transformed low-grade, or follicular large-cell lymphoma. Patients had a Karnofsky performance status of at least 60%, a granulocyte count of 1500 cells/mm³, a platelet count greater than or equal to 100,000/mm³, less than or equal to 25% of the intra-trabecular marrow space involved by lymphoma, and no evidence of progressive disease arising in a field irradiated with > 3500 cGy within one year of completion of irradiation.

Study 1 enrolled 40 patients with low-grade or transformed low-grade or follicular large-cell lymphoma whose disease had not responded to, or had progressed following, at least 4 doses of rituximab therapy. The median age was 57 years (range: 35 to 78 years); the median time from diagnosis to protocol entry was 50 months (range: 12 to 170 months); and the median number of prior chemotherapy regimens was 4 (range: 1 to 11). Overall, 35 of the 40 patients were rituximab-refractory (defined as no response or a response of less than 6 months' duration following rituximab therapy).

Study 2 enrolled 60 rituximab-naïve patients who had relapsed following or were refractory to chemotherapy. The median age was 60 years (range: 38 to 82 years), the median time from diagnosis to protocol entry was 53 months (range: 9 to 334 months), and the median number of prior chemotherapy regimens was 4 (range: 2 to 13). Fifty-three patients had not responded to prior therapy and 7 patients had responded with duration of response of less than 6 months.

The main outcome measure in Study 1 and Study 2 was overall response rate as determined by an independent panel that reviewed patient records and radiologic studies (Table 6).

Table 6: Efficacy Outcomes for the BEXXAR Therapeutic Regimen

The results of these studies were supported by demonstration of durable objective responses in 3 additional small, single-arm studies enrolling 130 rituximab-naïve patients with follicular non-Hodgkin's lymphoma with or without transformation. All patients had relapsed following, or were refractory to, chemotherapy. The overall response rates ranged from 49% to 64% and the median durations of response ranged from 13 to 16 months.

Last reviewed on RxList: 3/19/2012
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